This invention is directed to a method for use of a carbamate compound in the treatment of pain. More particularly, this invention is directed to a method for use of halogenated 2-phenyl-1,2-ethanediol monocarbamate or dicarbamate compounds for the treatment of pain.
Pain is generally defined as an unpleasant sensory and emotional experience, associated with actual or potential tissue damage (Wileman L, Advances in pain management, Scrip Report, 2000).
Acute pain is a physiological response to an adverse chemical, thermal or mechanical stimulus that may be associated with surgery, trauma or acute illness. These conditions include, but are not limited to, post-operative pain, sports medicine injuries, carpal tunnel syndrome, burns, musculoskeletal sprains and strains, musculotendinous strain, cervicobrachial pain syndromes, dyspepsia, gastric ulcer, duodenal ulcer, kidney stone pain, gallbladder pain, gallstone pain, dysmenorrhea, endometriosis, obstetric pain, rheumatological pain or dental pain.
Chronic pain is a pain condition beyond the normal cause of an injury or illness and may be a consequence of inflammation or serious, progressive, painful disease stages. Various types of chronic pain include, but are not limited to, headache, migraine, trigeminal neuralgia, temporomandibular joint syndrome, fibromyalgia syndrome, osteoarthritis, rheumatoid arthritis, bone pain due to osteoarthritis, osteoporosis, bone metastases or unknown reasons, gout, fibrositis, myofascial pain, thoracic outlet syndromes, upper back pain or lower back pain (wherein the back pain results from systematic, regional, or primary spine disease (radiculopathy)), pelvic pain, cardiac chest pain, non-cardiac chest pain, spinal cord injury-associated pain, central post-stroke pain, cancer pain, AIDS pain, sickle cell pain or geriatric pain.
Anticonvulsants have been effectively used for treating pain since 1940 when phenytoin, originally used for epilepsy, was demonstrated to have beneficial effects on trigeminal neuralgia. It has been well documented that carbamazepine, clonazepam, valproic acid, gabapentin, lamotrigine and topiramate, originally developed as anticonvulsants for treating epilepsy, have all shown efficacy for various chronic pain conditions including trigeminal, glossopharyngeal, superior-laryngeal and post-herpetic neuralgia, tabetic pain, phantom limb pain, prophylaxis of migraine, multiple sclerosis, thalamic syndrome, diabetic neuropathy and neuropathic pain (Swerdlow M, Anticonvulsant drugs and chronic pain, Clin. Neuropharmacol., 1984, 7, 51-82; Ettore B, The use of anticonvulsants in neurological conditions other than epilepsy: A review of the evidence from randomized controlled trials, CNS Drugs, 1999, 11, 1, 61-82; Leslie M, Nonepileptic uses of gabapentin, Epilepsia, 1999, 40 (Suppl. 6), S66-S72; Hansen HC, Treatment of chronic pain with antiepileptic drugs: a new era, Southern Medical Journal, 1999, 92, 7, 642-9). Anticonvulsants reduce excitability of neurons via their neurostabilizing properties, which may contribute to their efficacy in treating pain, since pain impulses are transmitted from nociceptors to the cerebral cortex via specific pathways throughout the spinal cord, brain stem and thalamus.
Substituted phenyl alkyl carbamate compounds have been described in U.S. Pat. No. 3,265,728 to Bossinger, et al (hereby incorporated by reference), as useful in treating the central nervous system, having tranquilization, sedation and muscle relaxation properties of the formula: 
wherein R1 is either carbamate or alkyl carbamate containing from 1 to 3 carbon atoms in the alkyl group; R2 is either hydrogen, hydroxy, alkyl or hydroxy alkyl containing from 1 to 2 carbons; R3 is either hydrogen or alkyl containing from 1 to 2 carbons; and X can be halogen, methyl, methoxy, phenyl, nitro or amino.
A method for inducing calming and muscle relaxation with carbamates has been described in U.S. Pat. No. 3,313,692 to Bossinger, et al (hereby incorporated by reference) by administering a compound of the formula: 
in which W represents an aliphatic radical containing less than 4 carbon atoms, wherein R1 represents an aromatic radical, R2 represents hydrogen or an alkyl radical containing less than 4 carbon atoms, and X represents hydrogen or hydroxy or alkoxy and alkyl radicals containing less than 4 carbon atoms or the radical: 
in which B represents an organic amine radical of the group consisting of heterocyclic, ureido and hydrazino radicals and the radical xe2x80x94N(R3)2 wherein R3 represents hydrogen or an alkyl radical containing less than 4 carbon atoms.
Optically pure forms of halogen substituted 2-phenyl-1,2-ethanediol monocarbamates and dicarbamates have also been described in U.S. Pat. No. 6,103,759 to Choi, et al (hereby incorporated by reference), as effective for treating and preventing central nervous system disorders including convulsions, epilepsy, stroke and muscle spasm; and as useful in the treatment of central nervous system diseases, particularly as anticonvulsants, antiepileptics, neuroprotective agents and centrally acting muscle relaxants, of the formulae: 
wherein one enantiomer predominates and wherein the phenyl ring is substituted at X with one to five halogen atoms selected from fluorine, chlorine, bromine or iodine atoms and R1, R2, R3, R4, R5 and R6 are each selected from hydrogen and straight or branched alkyl groups with one to four carbons optionally substituted with a phenyl group with substituents selected from the group consisting of hydrogen, halogen, alkyl, alkyloxy, amino, nitro and cyano. Pure enantiomeric forms and enantiomeric mixtures were described wherein one of the enantiomers predominates in the mixture for the compounds represented by the formulae above; preferably one of the enantiomers predominates to the extent of about 90% or greater; and, most preferably, about 98% or greater.
Halogen substituted 2-phenyl-1,2-ethanediol carbamate compounds of Formula (I) or Formula (II) have not been previously described as useful for the treatment of pain. Recent preclinical studies have revealed previously unrecognized pharmacological properties which suggest that a compound of Formula (I) or Formula (II) is useful in the treatment of pain. Therefore, it is an object of the present invention to teach a method for use of a compound of Formula (I) or Formula (II) in the treatment of pain.
The present invention is directed to a method for the treatment of pain comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of Formula (I) and Formula (II): 
wherein
phenyl is substituted at X with one to five halogen atoms selected from the group consisting of fluorine, chlorine, bromine and iodine; and,
R1, R2, R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen and C1-C4 alkyl; wherein C1-C4 alkyl is optionally substituted with phenyl (wherein phenyl is optionally substituted with substituents independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, nitro and cyano).
Embodiments of the invention include a method for the treatment of pain comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from the group consisting of Formula (I) and Formula (II).
Embodiments of the invention include the use of a compound selected from the group consisting of Formula (I) and Formula (II) for the preparation of a medicament for the treatment of pain in a subject in need thereof.
Embodiments of the method include the use of an enantiomer selected from the group consisting of Formula (I) and Formula (II) or enantiomeric mixture wherein one enantiomer selected from the group consisting of Formula (I) and Formula (II) predominates. For enantiomeric mixtures wherein one enantiomer selected from the group consisting of Formula (I) and Formula (II) predominates, preferably, one enantiomer selected from the group consisting of Formula (I) and Formula (II) predominates to the extent of about 90% or greater. More preferably, one enantiomer selected from the group consisting of Formula (I) and Formula (II) predominates to the extent of about 98% or greater.